tbuckley/cabot-search huggingface dataset:
Genomic landscape of SMARCA4-deficient lung tumors by clinical RNA sequencing.
Authors: Brian Pham, Weijie Ma, Greg Call, Arya Ashok, Elizabeth Mauer, Elham Kamangar, Tianhong Li
Journal: Journal of Clinical Oncology (2022)

3118 Background: SMARCA4-deficient lung cancer is an undifferentiated lung cancer subtype associated with poor prognosis and morphological features that make them challenging to distinguish from sarcoma. These tumors are known to be resistant to standard of care surgery, radiation, and chemotherapy. Recent case reports suggest that these tumors might be resistant to immunotherapy. An assessment of the genomic and transcriptomic features of SMARCA4-deficient thoracic tumors may identify potential novel targets and treatment strategies for this new WHO lung cancer classification. Methods: We retrospectively analyzed de-identified NGS data from 8,484 thoracic formalin-fixed, paraffin-embedded tumor biopsies from lung cancer patients sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). Tumor-normal match sequencing was performed for all tumors, enabling the detection of incidental germline alterations across 46 genes. SMARCA4-deficiency was defined as tumors with a pathogenic or likely pathogenic SMARCA4 single nucleotide variant, insertion/deletion, or copy number alteration. Statistical significance was determined using Fisher's exact test and Wilcoxon rank-sum tests. Results: SMARCA4-deficiency was detected in 370 (4.4%) tumors, of which over 80% were stage III or IV. SMARCA4-deficient tumors included more male patients (63% vs 49%, p &lt; 0.001) and younger age at diagnosis (median 64 vs 68 years, p &lt; 0.001). There were more patients with high tumor mutational burden (TMB-H, ≥10 mutations per megabase) (34% vs 15%, p &lt; 0.001), and fewer patients with positive PD-L1 immunohistochemical staining (44% vs 54%, p = 0.009) compared to SMARCA4 wild-type tumors. Microsatellite instability status occurred at similar low frequencies across SMARCA4-deficient vs wild-type tumors (0.8% vs 0.5%, p = 0.5). SMARCA4-deficient tumors showed enrichment for somatic mutations in TP53 (71% vs 47%, q &lt; 0.001), STK11 (22% vs 6.8%, q &lt; 0.001), KEAP1 (15% vs 4.2%, q &lt; 0.001), and CDKN2A (15% vs 5.9%, q &lt; 0.001) compared to wild-type. Tumor normal-match sequencing identified incidental germline mutations in MUTYH (2.2%), ATM (1.1%), ATP7B (0.5%), and MSH6 (0.5%) for SMARCA4-deficient tumors. RNA-sequencing analysis confirmed reduced transcriptional expression of SMARCA4 (p &lt; 0.001), CD274 (PD-L1; p &lt; 0.001), TNFRSF18 (p &lt; 0.001), and TNFRSF4 (p = 0.035) in deficient tumors vs wild-type. Furthermore, SMARCA4-deficient tumors revealed reduced infiltration of CD4+ T cells (19% vs 22%, p &lt; 0.001). Conclusions: This study reveals the unique genomic and transcriptional characteristics of SMARCA4-deficient lung tumors. Further studies are needed to assess the impact of immunotherapies and targeted therapies among this patient population.
Interface software can markedly reduce time and improve accuracy for clinical trial data transfer from EMR to EDC: The results of two measure of work time studies comparing commercially available clinical data transfer software to current practice manual data transfer.
Authors: Maureen Thompson, Len Grenier, Catarina Alvarez, Gary Poon, Jason M. Melear
Journal: Journal of Clinical Oncology (2022)

1573 Background: Clinical studies and new drug approvals are delayed by slow data transfer and transcription errors from site entered data. These delays have been compounded by a shortage of data entry personnel at sites such that data entry approaches 10-30 days post visit. Data transfer is largely performed by manual keyboard entry from electronic medical records (EMR) into electronic case report forms (ECRF). Methods: We conducted two separate measure-of-work time studies to compare a commercially available interface software product, ProXimity to the current manual data entry. The clinical trial data from two different EMRs (ARIA and IKM G2) to an EDC (Medidata Rave). The EDC mirrored an IRB approved clinical study. Time to transfer data and error rates were the primary and secondary endpoints, respectively. For study 1 Aria EMR data from 3 subjects and 1497 data fields including demographics, vital signs, ECOG PS, physical findings, adverse events, and lab results including CBC, CMP, urinalysis, coagulation, serology were selected for visits from Screening and C2D1. For Study 2 IKM G2 data from 6 subjects and 834 data fields included demographics, vitals, and lab results. The data entry personnel were aware of the timed nature of the study. Results: Study 1 ProXimity took 13.2 min to transfer the data compared to 73.4 min for manual entry, with error rates of 0.8% compared to 3.5%, respectively. In Study 2 Proximity took 6.5 min compared to 29 min for manual entry, with error rates of 1.4% each due to non- conformant data (text). Conclusions: Software data transfer interfaces can markedly shorten the time for data entry, reduce error rates and reduce operational costs.
Resistance to anti-PD-1/anti-PD-L1: GB1211 reverses galectin-3 induced blockade of pembrolizumab and atezolizumab binding to PD-1/PD-L1.
Authors: Joseph Mabbitt, James A. Roper, Robert John Slack
Journal: Journal of Clinical Oncology (2022)

2607 Background: Galectin-3 (Gal-3) is a β-galactoside binding lectin highly expressed across many cancers (Li et al. Biomedicines, 2021) with high expression associated with poor response to the PD-1 inhibitor pembrolizumab (Capalbo et al., Int J Mol Sci, 2019). In addition, it has also been shown preclinically in in vivo mouse non-small cell lung carcinoma (NSCLC) models that inhibition of Gal-3 enhances the performance of checkpoint inhibitors targeting the PD-1/PD-L1 axis (Vuong et al., Cancer Res, 2019; Zhang et al., FEBS Open Bio, 2020). The mechanism by which Gal-3 negatively impacts the effect of PD-1/PD-L1 based checkpoint inhibitors is not fully understood. We investigated the hypothesis that anti-PD1/anti-PDL1 is induced by direct binding and blockade of Gal-3 to the PD-1/PD-L1 complex itself. Methods: SPR was used to investigate the effect of recombinant hGal-3 in combination with a Gal-3 inhibitor (GB1211) on the binding of recombinant hPD-L1 to hPD-1 in the absence and presence of either pembrolizumab or atezolizumab. SPR analysis was performed with a BIAcore (Cytiva, USA). hPD-1 was immobilized onto a CM5 Series S sensorchip via amine coupling and proteins, antibodies or small molecules flowed over in various combinations. Observations made at the protein level were further confirmed in cell binding assays using flow cytometry measuring pembrolizumab and atezolizumab binding to cells lines over expressing high levels of either PD-1 (Jurkat cells) or PD-L1 (RAJI-hPD-L1 cells), respectively. Results: Gal-3 potentiated the binding of PD-L1 to PD-1 with a 3-fold increase in its K D observed and the efficiency of pembrolizumab and atezolizumab binding to and blocking the PD-1/PD-L1 axis was reduced. A 6-fold reduction in K D of pembrolizumab for the PD-1/PD-L1 complex was observed in the presence of Gal-3. In addition, atezolizumab PD-L1 blockade was reversed in the presence of Gal-3 and dramatically improved by GB1211. Similarly, in cell systems expressing high levels of PD-1 or PD-L1, Gal-3 reduced the binding of pembrolizumab and atezolizumab to their respective targets on cell surfaces that was also reversed by GB1211. Conclusions: Gal-3 was shown to vastly reduce the binding of the checkpoint inhibitors pembrolizumab and atezolizumab, by potentiating the interaction between PD-1 and PD-L1. GB1211 restored the binding of the anti-PD1/anti-PDL1 therapeutics and may thus reduce tumor resistance to these agents. These findings harmonize excellently with in vivo and clinical data showing an association between Gal-3 expression and lack of efficacy of PD-1/PD-L1 targeted checkpoint inhibitors. Galecto is now investigating the safety and efficacy of GB1211 in combination with atezolizumab in NSCLC.
Triple negative breast cancer presentation in Afro-Caribbean women in New York City.
Authors: Ana M Ventura, Evelyn Taiwo, Harshraj Leuva, Edwin Chiu
Journal: Journal of Clinical Oncology (2022)

e18726 Background: In the United States, triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancers. It also has a higher incidence and worse prognosis in black women. There is paucity of information on the incidence and presentation of breast cancer in black women from the Caribbean. The clinical and pathologic profile of TNBC in this immigrant underrepresented patient group is described here. Methods: This is a retrospective study performed at Kings County Hospital (KCH), a safety net hospital in Central Brooklyn, New York City with a predominantly Afro-Caribbean patient population. Data from patients diagnosed with breast cancer from 2015-2018 were collected from the institution’s tumor registry and the clinical and pathologic data of these patients were collected and analyzed with descriptive statistics and chi square testing. Results: Of the total 299 female patients with a breast cancer diagnosis, 60 patients (20%) had TNBC with median age 57 and Nottingham grade 3 in 90% (54) of the patients. At presentation, 43% (26) presented with localized disease, 55% (33) with lymph node involvement (regional), and 2% (1) with distant metastasis. When stratified by menopausal status, 46 patients (77 %) were post-menopausal and remainder pre-menopausal. Premenopausal women presented with higher rates of regional disease at 64% with compared to 50% in the postmenopausal women (p = 0.5444). BMI was similar in both groups (p = 0.9879). Of the 37 patients with documented country of origin, 84% (31) were from the Caribbean, and 27% of these patients identified as medical tourists from the Caribbean. 25% (15) of all patients reported 1 st or 2 nd degree relative with breast cancer and 18% (11) reported a first degree relative with malignancy other that breast cancer. 100% of patients younger than 44 years reported a family history of cancer. Genetic testing information was unavailable to these patients. Of the twenty patients (33%) that received neoadjuvant chemotherapy with standard treatment, two achieved complete response, 15 partial response, and 3 without response to treatment. Conclusions: In our study of African-Caribbean patients with breast cancer, the incidence of TNBC was high at 20% with most presenting with high-grade tumors, regional lymph node involvement, and young age at diagnosis. Notably this represents a high-risk cohort with significant family history of breast and other cancers suggestive of inherited or familial cancers. Response to standard neoadjuvant chemotherapy was less than expected, encouraging the need to consider neoadjuvant immunotherapy in these patients.
Modifiable risk factors for late mortality among five-year survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Stephanie B Dixon, Qi Liu, Matthew J. Ehrhardt, Eric Jessen Chow, Kevin C. Oeffinger, Ann C. Mertens, Paul C. Nathan, Rebecca M. Howell, Wendy M. Leisenring, Kevin R. Krull, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Yutaka Yasui, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2022)

10014 Background: The impact ofmodifiable lifestyle and cardiovascular risk factors (CVRFs) on risk for late mortality in adult survivors of childhood cancer is not well established. Methods: All-cause and health-related late (&gt;5 years from cancer diagnosis) mortality (HRM; excludes death from primary cancer and external causes) were evaluated in five-year survivors diagnosed &lt;21 years of age using the National Death Index through 2017. Modifiable lifestyle (smoking status, alcohol use, physical activity, body mass index [BMI]; combined to create a score [0-4] and categorized as unhealthy [0-2], moderate [2.5 or 3], healthy [3.5 or 4]) and CVRFs (hypertension [HTN], diabetes [DM], dyslipidemia) were assessed as time-varying covariates. Standardized mortality ratios (SMRs) and absolute excess risk of death per 1000 person-years (AER) with 95% confidence intervals (CIs) were estimated. Multivariable models estimated the relative risk (RR) of death adjusted for demographic and socioeconomic variables. Results: Among 20,051 adult survivors (median age 40.0 years, range 18.7 – 67.7), 19% reported ≥1 CVRF (13% HTN, 9% dyslipidemia, 5% DM) and few reported a healthy lifestyle (29% healthy, 40% moderate, 31% unhealthy). There were 1476 deaths due to health-related causes. While all survivors experienced an increased risk of HRM compared to the US population, risk was lower among those with a healthy vs. unhealthy lifestyle (SMR 3.5, 95% CI 3.1-3.9 vs. 6.2, 5.7-6.7) and very high among underweight survivors (11.1, 9.3-13.3) and those with both HTN and DM (13.0, 9.2-18.0). Stratified by lifestyle score, the excess risk of HRM was lowest in those with a healthy lifestyle across survival time (Table). Similar trends were seen when stratified by 0, 1 and 2 CVRFs. In multivariable models, compared to survivors with no CVRFs and healthy lifestyle, no CVRFs and unhealthy lifestyle was associated with a 50% increased risk of HRM (RR 1.5, 95% CI 1.2-1.8) and unhealthy lifestyle plus HTN a 2-fold increased risk of HRM (2.2, 1.6-2.8). Regardless of lifestyle group, ≥2 CVRF increased risk for HRM at least 2-fold (p-values &lt;0.001). Conclusions: A reduction in excess deaths is observed among adult survivors of childhood cancer with a healthy lifestyle and no CVRFs as they age. Interventions that target improved lifestyle choices and prevention or aggressive treatment of modifiable CVRFs may reduce risk for late mortality. [Table: see text]
Predictive factors for cancer treatment delay in an underserved urban population.
Authors: Risha Sheni, Jiyue Qin, Shankar Viswanathan, Enrico Castellucci, Vikas Mehta
Journal: Journal of Clinical Oncology (2022)

e18608 Background: Incremental delays in cancer time to treatment initiation (TTI) have been shown to cause a proportional, independent increased risk of disease specific mortality for breast cancer, colorectal cancer (CRC), head and neck (HNC), non-small cell lung cancer (NSCLC) and pancreatic cancer. A portion of delays can be attributed to increasingly complex workup with modern imaging, genomic, and multidisciplinary/multimodality treatment paradigms. However, studies suggest delays are associated with racial and socioeconomic disparities, implicating a target for addressing inequitable care. Given Montefiore Medical Center (MMC) serves a racially diverse, socioeconomically challenged population, we sought to evaluate the association between patient factors and TTI to identify factors associated with TTI delay. Methods: Retrospective cohort study at an urban community-based academic center of patients diagnosed with or referred for curative intent treatment of breast cancer, CRC, HNC, NSCLC, and pancreatic cancer at MMC from January 2019 to December 2021. Variables of interest included tumor staging, primary treatment modality, marital status, Charlson Comorbidity Index (CCI) score, tobacco use, zip code, insurance type, language preference, primary care provider status, and inpatient (IP) admission or emergency room visit 30 days prior to diagnosis. Results: A total of 3430 patients (F=2376, M=1054) were identified (mean age 64.2 ± 13.3). Demographics are summarized in Table. The Median TTI was 21 days (7, 41 IQR). In assessing factors associated with TTI delay, patients who were IP 30 days before diagnosis were significantly more likely to have timely TTI for breast cancer (p&lt;0.003), CRC (p&lt;0.001), HNC (p&lt;0.006), and NSCLC (p&lt;0.001). For CRC, a higher CCI score was associated with TTI greater than 30 days (p&lt;0.019). For lung cancer, older age (p&lt;0.015) and having public insurance (p&lt;0.001) were associated with TTI delay. Conclusions: IP admission 30 days before diagnosis was associated with timely TTI for breast cancer, CRC, HNC, and NSCLC. Other factors predictive of delay included CCI score in CRC, and advanced age at diagnosis and insurance type for NSCLC. This study identifies factors predicting delay and opportunities for addressing delay, thereby improving survival outcomes in our population.[Table: see text]
Clinical significance of next generation sequencing (NGS) in Chinese patients with relapsed/refractory Wilm’s tumor.
Authors: Juan Wang, Huizi Chai, Lele Zhao, Xueyu Yang, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e22014 Background: Medical advances have been greatly improved in the five-year survival rate for Wilms’ tumor, but the survival is still dismal for relapsed/refractory (R/R) patients. In the present study, we aimed to investigate the genomic profiling and the incidence of germline cancer susceptibility mutationsof Chinese patients with R/R WT. Methods: Next-generation sequencing (NGS) of tumor specimens with matched blood samples obtained from R/R pediatric WT in Sun Yat-Sen University Cancer Center were used in a CAP-certified laboratory (Simcere Diagnostic Co, Ltd). Clinical information including age, gender and tumor histology were collected. Somatic and germline mutations including single nucleotide variants (SNV), insertion-deletion variants (Indels), copy number variations (CNVs) and fusion, as well as tumor mutational burden (TMB) were analyzed. Results: Nineteen patients with R/R WT were enrolled in this study, including 10 males and 9 females, with a median age of 4 years old (range, 0-14). All of the pathology was identified as favorable histology WT (FHWT). Somatic mutations were detected in 84.21% (16/19) of patients, and CNVs accounted for the majority of the total somatic aberrations, followed by SNVs. The most common somatic mutations were identified in the following genes, CTNNB1 , ERBB2, MCL1 , CDK2 and MDM4. Of the top 3 frequently mutated genes, the mutation frequency and their most common mutation type were CTNNB1, 26%, in-frame deletion, missense mutation; ERBB2 21%, missense mutation, amplification; MCL1 21%, amplification. It is worth noting that MCL1 mutation has never been reported in Chinese R/R WT patients before, which may be a potential valuable mechanism. Germline mutations were detected in 89.47% (17/19) of patients, and CNVs accounted for the majority of the total germline aberrations, followed by SNVs. The most common germline mutations were identified in the following genes, MCL1, RET, ALK, EPCAM, and FANCA. Of the top frequently mutated genes frequency and most common mutation type were MCL1 21%, amplification; RET 21% missense mutation, multiple mutations. There are also some suspected clinically pathogenic germline mutation of genes CDK4 , ERBB2, and MDM4 . All the mutation type were amplification. Notable cancer driver mutations were also characterized, such as the amplifications of ERBB2 / MET/EGFR / FGFR1, and the point mutations of CHEK2/FBXW7/NF1. The median TMB was 1.47 (range, 0-7.8). Conclusions: Overall, clinical and new results were detected in 14 (73.68%) in Chinese R/R WT patients. We discovered some driver genes mutations which potentially sensitive to the corresponding targeted drugs in Chinese R/R WT patients. Large sample size was needed to provide a better understanding of molecular features in R/R WT patients to achieve precision medicine.
The mutational pattern of DNA damage repair pathway in pancreatic cancer patients.
Authors: Yanfang Song, Huina Wang, Huanhuan Liu, Yanrui Zhang, Mingwei Li, Feng Lou, Shanbo Cao
Journal: Journal of Clinical Oncology (2022)

e16293 Background: Besides BRCA1/2, there are various genes involved in DNA damage repair that could predict patients’ response to treatments such as platin-based therapy, PARP inhibitors, and immunotherapy. While the mutational pattern of DNA damage repair (DDR) gene alterations in pancreatic patients remains unknown. Methods: Tumors and blood samples from 490 pancreatic patients were analyzed with next-generation sequencing (NGS) that covered 808 genes. Patients were classified based on the presence or absence of deleterious mutations across a panel of 98 DDR genes. Results: 70.4% (345/490) pancreatic cancer patients harbored DDR gene pathogenic mutations (mut). Among DDR-mut patients, 84.6% (292/345) had only somatic DDR gene alterations, 6.4% (22/345) had only germline DDR gene alterations, and 9.0% (31/345) had both. The most frequently mutated somatic DDR genes were TP53 (73.9%), CDKN2A (17.1%), ARID1A (10.1%), ATM (4.1%), and BRCA2 (4.1%). The most commonly mutated germline DDR genes were BRCA2 (4.1%), RAD51B (2.0%), ATM (2.0%), FANCE (0.9%), PALB2 (0.9%). Among the functional pathways of DDR genes, the most commonly mutated pathways were others (77.2%), FA (10.1%), CCC (7.7%), HR (1.5%), NHEJ (1.4%), MMR (1.4%), and BER (0.8%). No patients were found to harbor mutations in NER, TLS, and DR pathways. In addition, the mean TMB was significantly higher in the DDR-mut group compared with the wild-type DDR (wt) group (6.2 vs. 5.0 muts/Mb; p &lt; 0.05). No significant difference in microsatellite instability was observed between DDR-mut and DDR-wt patients (p = 0.67). In terms of HRD status, 87.5% (28/32) HRD-positive patients and 73.1% (19/26) HRD-negative patients had DDR gene mutations. No significant difference in DDR variants was found between HRD-positive and HRD-negative patients, suggesting that HRD detection is necessary for DDR-mut patients. Within individual DDR genes, CDKN2A mutation was significantly associated with HRD-positivity (p &lt; 0.05) whereas BRCA1, BRCA2, ATM, and PALB2 were not. Conclusions: An expanding set of DDR genes profiling provides more therapeutic opportunities for pancreatic patients who might benefit from PARP inhibitor owing to pathogenic mutations in DDR genes. This retrospective study may serve as a benchmark for the future design of an expanded association study between DDR mutations and the therapeutic outcome of pancreatic cancer.